Processes for the synthesis of O-desmethylvenlafaxine

ABSTRACT

Provides are intermediates and processes for preparation of o-desmethylvenlafaxine.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the following U.S. Provisional Patent Application Nos. 60/833,616, filed Jul. 26, 2006; 60/837,879, filed Aug. 14, 2006; 60/849,216, filed Oct. 3, 2006; 60/843,998, filed Sep. 11, 2006; 60/849,255, filed Oct. 3, 2006; 60/906,639, filed Mar. 12, 2007; and 60/906,879, filed Mar. 13, 2007. The contents of these applications are incorporated herein by reference.

FIELD OF THE INVENTION

The invention encompasses a process for the synthesis of O-desmethylvenlafaxine.

BACKGROUND OF THE INVENTION

Venlafaxine, (±)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol is the first of a class of anti-depressants. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin, and is an alternative to the tricyclic anti-depressants and selective re-uptake inhibitors. Venlafaxine has the following chemical formula, Formula I:

O-desmethylvenlafaxine, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, is reported to be a metabolite of venlafaxine and has been reported to inhibit norepinephrine and serotonin uptake. See Klamerus, K. J. et al., “Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite,” J. Clin. Pharmacol. 32:716-724 (1992). O-desmethylvenlafaxine has the following chemical formula, Formula II:

Processes for the synthesis of O-desmethylvenlafaxine, comprising a step of demethylation of the methoxy group of venlafaxine, are described in U.S. Pat. Nos. 7,026,508 and 6,689,912, and in U.S. publication No. 2005/0197392.

The synthesis disclosed in the above references is performed according to the following scheme:

Wherein “MBC” refers to methyl benzyl cyanide, “CMBC” refers to cyclohexyl methylbenzyl cyanide, “DDMV” refers to didesmethyl venlafaxine, and “ODV” refers to O-desmethylvenlafaxine.

However, the processes disclosed in the above U.S. patents and U.S. patent applications all remain problematic when applied to industrial scale production. The process in U.S. Pat. No. 7,026,508 uses L-selectride, a compound which is very problematic when scaling up the process for industrial application. Further, the process disclosed in US Application Publication No. 2005/0197392 uses lithiumdiphenyl phosphine, a compound which handling and use in industrial scale processes is extremely dangerous. Also, the process disclosed in U.S. Pat. No. 6,689,912 uses methanol as a solvent, which use is problematic when traces of methanol remain and in subsequent process steps when high temperatures are applied.

There is a need in the art for a new synthetic route for obtaining sO-desmethylvenlafaxine, using a precursor of venlafaxine to directly obtain O-desmethylvenlafaxine.

SUMMARY OF THE INVENTION

In one embodiment, the invention encompasses (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).

In one embodiment the present invention provides a process for preparing CBBC comprising reacting BBC with cyclohexanone.

In another embodiment, the present invention provides a process for preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) comprising precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), a dry organic solvent, a base and cyclohexanone.

In another embodiment, the present invention provides a process for obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), a phase transfer catalyst, a base and cyclohexanone.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and further converting the CBBC to O-desmethylvenlafaxine.

In another embodiment, the invention encompasses 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).

In another embodiment, the present invention provides a process for preparing 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) comprising: combining CBBC, an organic solvent and borane to create a reaction mixture, followed by recovery of the BDDMV from the reaction mixture.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine.

In another embodiment, the invention encompasses 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).

In another embodiment, the present invention provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, followed by recovery of the BODV from the reaction mixture.

In another embodiment, the present invention provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, an organic solvent, and a methylating agent to form a mixture, and recovering the BODV from the mixture.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In one embodiment the present invention provides a process for preparing O-desmethylvenlafaxine comprising combining BODV with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocuprate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine.

In another embodiment, the invention encompasses hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).

In another embodiment, the present invention provides a process for preparing hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine.

In another embodiment, the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.

The present invention further provides processes for preparing O-desmethylvenlafaxine via the intermediates described above.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses a new synthetic route for obtaining O-desmethylvenlafaxine, from 4-bromophenylacetonitrile (BBC), (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC), 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV), 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) and hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).

In the process of the invention, the intermediate bromophenylacetonitrile (BBC) is condensed with cyclohexanone to form the intermediate (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC). Further, the cyano group on the CBBC is subjected to reduction, to form the intermediate 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) which is then subjected to selective alkylation to produce 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV), which is finally converted to O-desmethylvenlafaxine (ODV), by performing halide exchange (optionally, the final conversion step can go via a protected BODV intermediate) as described in the following scheme:

where x is a suitable hydroxy protecting group.

The use of precursors of venlafaxine which contain a halogen group, in the new synthetic route for obtaining O-desmethylvenlafaxine, highly improves the yield of the reaction.

In one embodiment, the invention encompasses (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC). Also provided is CBBC in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The CBBC may have a purity of at least about 50% as measured by HPLC. The compound is characterized by NMR ¹H (DMSO-d₆) δ: 1.56 (4H, H cyclohexyl), 1.71 (2H, H cyclohexyl), 2.25 (2H, H cyclohexyl), 2.61 (2H, H cyclohexyl), 3.32 (1H, CHCN), 7.27 (2H, H arom.), 7.65 (2H, H arom.).

The present invention also provides a process for preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) by reacting BBC with cyclohexanone

This process can comprise precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), organic solvent, a base and cyclohexanone. Preferably the organic solvent is dry. An organic solvent is dry if it is essentially free of water such that the amount of residual water, if detectable, does not interfere with the reaction (e.g. by destroying catalysts or reagents) in a manner that prevents the benefits of the present invention from being realized. Typically an organic solvent having less than 1% by water is considered to be dry by one of ordinary skill of art.

Preferably, the dry organic solvent is selected from the group consisting of: C₄₋₈ ethers, polar aprotic solvents (Polarity Index of greater than about 2.0), C₁-C₈ chlorinated aliphatic, C₆-C₁₂ aromatic hydrocarbons, and C₁₋₆ alcohols. More preferably, the ethers are selected from the group consisting of: diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), the polar aprotic solvents are selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO), the chlorinated organic solvents are selected from the group consisting of methylene chloride and chlorobenzene or chloroform and the aromatic hydrocarbons are selected from the group consisting of toluene and benzene. Most preferably, the dry organic solvent is selected from the group consisting of: tetrahydrofuran (THF), methanol, methylene chloride and toluene. The organic solvent can be used individually, or in a mixture with another solvent, particularly methanol.

The base can be an inorganic base, such as an alkali metal or alkaline earth metal. More preferably, the base is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis(trimethyl silyl) amide (LiN[(CH₃)₃Si]₂), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH₃). The base is preferably present in an amount of about 1 to about 5 moles per mole of BBC.

The process can be carried out by combining a solution or a slurry of BBC and a dry organic solvent with a base to obtain a reaction mixture, followed by combining the reaction mixture with cyclohexanone, to obtain CBBC. Cyclohexanone can be added to the reaction mixture in a dropwise manner. After combining the reaction mixture with cyclohexanone, the mixture is further maintained, until completion of the reaction.

CBBC may then be recovered. The solvent can be evaporated and the residue dissolved in a water immiscible solvent such as toluene, EtOAc (ethyl acetate), CH₂Cl₂, diethyl ether, MTBE (methyl-t-butyl ether), MEK (methyl ethyl ketone) washed with water or brine, and evaporated to get an oil. The oil can then be added to an organic solvent such as methanol to obtain a solution and crystallize CBBC.

In another embodiment, the present invention provides a process for obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), optionally a phase transfer catalyst, a base and cyclohexanone. The reaction may occur with or without the presence of an organic solvent or water. Preferably, the reaction occurs in the presence of water. The use of water allows for obtaining a product that otherwise would be contaminated with residual organic solvent.

The phase transfer catalyst can be a tetraalkylammonium, tetraalkylphosphonium, tetraarylammonium or tetraarylphosphonium, preferably wherein the alkyl group can be the same or different and contains from 1 to 10 carbons, and wherein the aryl group can be the same or different and contains from 6 to 8 carbons.

The phase transfer catalyst can be a tetraalkylammonium halide, preferably wherein the alkyl group can be the same or different and contains from 1 to 6, preferably from 1 to 4 carbon atoms, and the halide is fluoride, chloride, bromide or iodide, preferably chloride, bromide or iodide.

Preferably, the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot, quaternary ammonium salt, quaternary phosphonium salt and crown ether. More preferably, the phase transfer catalyst is tetra butyl ammonium bromide (TBAB).

The base may be an inorganic base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, preferably, NaOH, KOH, LiOH, CsOH, K₂CO₃ or NaCO₃, Cs₂CO₃, KHCO₃ or NaHCO₃

BBC, cyclohexanone, the phase transfer catalyst such as TBAB and the base such as NaOH are combined. Preferably, the base is added in an amount of about 0.5 to about 1 mole per mole of BBC. The cyclohexanone is added in an amount of about 1 to about 1.15 moles per mole of BBC. The reaction is then maintained to get CBBC. The reaction can be maintained from about 1 to about 24 hours. It can also be stirred while maintained.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and further converting the CBBC to O-desmethylvenlafaxine.

In another embodiment, the invention encompasses 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV). Also provided is BDDMV in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BDDMV may have a purity of at least about 50% as measured by HPLC.

BDDMV can be prepared by reacting CBBC with a reducing agent. More specifically, BDDMV can be prepared by combining CBBC an organic solvent such as THF to obtain a solution, to which a reducing agent is added. Preferably the solvent is a dry organic solvent, as described above, more preferably THF. Chlorinated solvents, such as C₁-C₈ chlorinated hydrocarbons and C₄-C₈ ethers can also be used. Preferably the reducing agent is borane or a hydride, more preferably a Borane dimethylsulfide complex, which is added dropwise. Preferably, the borane is present in an amount of about 1 to about 3 moles per mole of CBBC. Alternatively, the reducing agent may be H₂ in presence of catalyst such as Ni or Co or Pt. The resulting reaction mixture can then be maintained, preferably for about 1 hr to about 48 hrs, such as about 12 hours. This mixture can then be quenched such as by adding NH₄Cl and hydrogen peroxide.

The BDDMV can then be recovered. The resulting layers may be separated and the organic layer acidified, such as with citric acid. Optionally, the aqueous phase can be basified such as with NH₄OH and extracted with diethylether to recover more of the product. The organic layer can then be washed with brine or water to remove water soluble impurities, and dried. Drying can be carried out over Na₂SO₄ or under a pressure of less than one atmosphere, or both.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine.

In another embodiment, the invention encompasses 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). Also provided is BODV in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BODV may have a purity of at least about 50% as measured by HPLC.

The present invention also provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). BODV may be prepared by reductive amination reaction of BDDMV and a formaldehyde source in the presence of a reducing agent. In one embodiment this process comprises combining BDDMV, formaldehyde and a reducing agent. BODV is then recovered from the obtained reaction mixture.

BDDMV, such as that prepared above, can be dissolved or suspended (preferably dissolved) in a C₁₋₄ alcohol such as MeOH. Formaldehyde, preferably in the form of a formalin solution is then added to obtain a solution. Formaldehyde in water can also be used as a solvent. A reducing agent, preferably NaBH₄ or formic acid is then added. The reaction is an exothermic reaction, so prior to combining the sodium borohydride with the formaldehyde solution, formaldehyde solution is preferably cooled to a temperature of less than about 10° C. Preferably, the reaction mixture is maintained, while stirring, for about 1 to about 24 hours, such as about 12 hours. Preferably, the formaldehyde is present in an amount of from about 1 mole per mole of BDDMV, to an excess amount, such as about 50 moles. Preferably, the sodium borohydride is present in an amount of about 1 mole per mole of BDDMV.

The BODV can then be recovered. Recovery can be carried out by evaporating the organic solvent, such as under reduced pressure, to obtain a residue. The residue can then be dissolved in a water immiscible organic solvent such as methylene chloride EtOAc, toluene, MEK, TBME, diethyl ether and acidified to a pH of about 2 to about 6. An inorganic acid such as HCl or H2SO4 can be used. Optionally the aqueous phase is basified to a pH of about 8 to about 10 to facilitate extraction of additional amounts of BODC. NH₄OH can be used as a base and methylene chloride as a solvent for extraction. The organic phase can then be evaporated, such as under a pressure of less than about one atmosphere, to obtain BODV.

BODV can also be prepared by a process which comprises combining BDDMV, an organic solvent, and a methylating agent. BODV is then recovered from the obtained reaction mixture.

BDDMV, such as that prepared above, is dissolved in an organic solvent, preferably dichloromethane or dimethylsulfoxide. Optionally a base is added to the solution. The base can be BuLi or a C₃-C₉ trialkylamine such as triethylamine. Alkali metal or alkaline earth metal hydrides or hydroxides such as NaH and NaOH can also be used. If an inorganic base is used, an inert organic solvent may also be added. For example, with BuLi can be added as a solution in a C₅-C₁₂ saturated (aliphatic) or aromatic hydrocarbon, such as hexane. A methylating agent is added. Preferably the methylating agent is a methyl halide, preferably methyl iodide. Dimethylsulfate can also be used. The reaction can be done as neat reaction, methyliodide being the solvent and the reagent. Preferably, the organic solvent is dichloromethane or dimethylsulfoxide or THF. The mixture can then be maintained for about 30 minutes to about 16 hours to obtain BODV. The BODV can then be recovered.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.

Preferably, the hydroxide donor base is an alkali metal or alkaline earth metal hydroxide, such as potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydroxide (NaOH), cesium hydroxide. Preferably, the metal salt is silver nitrate (AgNO₃). Optionally, the AgNO₃ is employed into the reaction mixture, as a supported AgNO₃. The term “supported AgNO₃” as used herein refers to Montmorillonite. Silica can also be used as support. Montmorillonite is a very soft phyllosilicate mineral that typically forms in microscopic crystals, forming a clay. Preferably, the hydroxide donor base is present in an amount of about 1 to about 20 moles per mole of BODV. Preferably, the metal salt is present in an amount of about 1 to about 20 by weight of BODV.

As exemplified, to a solution of AgNO₃ in water montmorillonite is added and the resulting mixture is heated. Heating is preferably carried out to a temperature of about 40 to about 150° C., such as about 100° C. for 1 hour. The solution can then be dried, such as by heating, or reducing the pressure to less than about one atmosphere. Then, BODV, and a base such as NaOH and the supported AgNO₃ are combined. Preferably, the reaction mixture is heated to a temperature of above 20° C.; more preferably, the reaction mixture is heated to about 100° C. Preferably, the obtained reaction mixture is maintained, while stirring, for about 18 hours. ODV can then be extracted from the reaction mixture with an organic solvent, such as with a mixture of chloroform and methanol. Other solvents such as EtOAc, THF, or acetone can also be used.

The present invention further provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or a organocuprate reaction. In one embodiment, BODV is combined with Mg, a halogen (only Mg or Cu in case of organo cuprate reaction) and a dry organic solvent to provide a Grignard reagent. Such synthetic step is known by one skilled in the art as Grignard reaction. The Grignard reagent is then combined with borate and an acid to provide O-desmethylvenlafaxine.

In one embodiment, Mg and a halogen such as I₂ are combined with BODV in an inert solvents organic solvent such as THF, CH₂Cl₂, ACN, ethers. The BODV can be added dropwise. The mixture can then be heated, such as to a temperature of about 30 to about reflux, more preferably about reflux. Before adding borate, the mixture is preferably cooled, such as to about −20 C, to about 10 C, preferably about −10 C. Trimethylborate is then added. After stirring an organic or inorganic acid, such as glacial acetic acid is added. The reaction mixture can then be quenched, such as by adding hydrogen peroxide. For recovery, a water immiscible solvents organic solvent, such as Diethylether, EtOAc, TBME, toluene, MEK, is added to the reaction mixture to obtain ODV. The solvent can then be removed such as by reducing the pressure to less than one atmosphere.

Optionally, the new synthetic route for obtaining O-desmethylvenlafaxine can go via a protected intermediate of BODV.

The protected intermediate of BODV may contain any suitable hydroxyl protecting group, such as silyl, acetyl and dihydropyran (DHP).

In another embodiment, the invention encompasses hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P). Preferably, the BODV is protected with an acetyl. Also provided is BODV-P, particularly acetyl protected, in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BODV-P including acetyl protected may have a purity of at least about 50% as measured by HPLC.

In another embodiment, the present invention provides a process for preparing hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.

Typically, the solvent used can be any organic solvent. Preferably, the organic solvent is ethyl acetate. Other organic solvents such as CH₂Cl₂, ethers such THF, toluene, hexane or ACN can also be used.

Preferably, the process is performed under basic conditions. Typically, the basic source is organic or inorganic base. Preferably, the basic source is a C₃-C₉ trialkyl amine such as triethylamine or imidazole or lutidine or pyridine. An inorganic base such as an alkali metal or alkaline earth metal carbonate such as K₂CO₃ can also be used,

Preferably, the protecting agent is selected from the group consisting of: silyl, acetyl, DHP and derivatives thereof. More preferably, the protecting agent is acetyl chloride or acetic anhydride. The reaction mixture is optionally maintained for about 30 minutes to about 24 hours to obtain BODV-P. BODV-P may then be recovered from the reaction mixture by any method known in the art.

One of ordinary skill of art would appreciate that each of the above processes described for preparation of CBBC, BDDMV, BODV, BODV-P and ODV can be combined. Such combination can be combining the process of CBBC, with BDDMV to prepare BODV, and further to prepare BODV-P if desired, and further to prepare ODV. Such process can also start with BDDMV, BODV or BODV-P. Such combinations are provided in further detail below.

In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine.

In another embodiment, the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction.

The conversion can be performed as described above for BODV.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, a hydroxide donor base and a metal salt. O-desmethylvenlafaxine is then be recovered from the reaction mixture.

The hydroxide donor base and a metal salt used in the reaction are as described above.

One of ordinary skill of art would appreciate that each of the above processes described for preparation of CBBC, BDDMV, BODV, BODV-P and ODV can be combined. Such combination can be combining the process of CBBC, with BDDMV to prepare BODV, and further to prepare BODV-P if desired, and further to prepare ODV. Such process can also start with BDDMV, BODV or BODV-P. Such combinations are provided in further detail below.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.

The invention in certain of its embodiments is illustrated by the following non-limiting examples.

EXAMPLES Preparation of CBBC Example 1

A 250 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged slowly with MeOH (50 ml) and NaOCH₃ (10 g, 185 mmol) at ambient temperature. DMF (4 ml) and Bromophenylacetonitrile (20 g, 102 mmol) were added. The reaction mixture was stirred at ambient temperature until complete dissolution. Cyclohexanone (20 g, 203 mmol) was then added dropwise and the reaction was stirred at ambient temperature overnight. The solvent was evaporated and the residue was dissolved in toluene, washed with brine and evaporated to get an oil which on crystallization from MeOH yielded CBBC.

Example 2

A 100 ml three necked flask equipped with, thermometer and mechanical stirrer is charged with BBC (2 g, 10 mmol), cyclohexanone (2 g, 20.3 mmol), TBAB (0.2 g) and NaOH (6 ml 10%). The reaction is stirred at RT overnight to get CBBC.

Preparation of BDDMV Example 3

A 250 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with CBBC (7 g, 23.79 mmol) and THF (100 ml). This solution was stirred at ambient temperature. Then a solution of Borane dimethylsulfide complex (20 ml 2M in THF, 39.89 mmol) was added dropwise. This mixture was stirred overnight at ambient temperature and poured into saturated solution of NH₄Cl. A 30% solution of hydrogen peroxide was then added. The layers were separated and the organic layer was acidified with citric acid.

The aqueous phase was basified with NH₄OH and extracted with diethylether. The organic layer was then washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure to get BDDMV.

Preparation of BODV Example 4

BDDMV (0.81 g, 2.72 mmol) was dissolved in MeOH (20 ml). A formalin solution (1.3 ml, 16.25 mmol) was added and the solution was cooled with an ice bath. To the cold solution NaBH₄ (0.25 g, 6.5 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and the solvent was then evaporated under reduced pressure. The residue was dissolved in methylene chloride and acidified with 10% HCl. The aqueous phase was basified with NH₄OH and extracted with methylene chloride. The organic phase was then evaporated under reduced pressure to get BODV.

Example 5

BDDMV (0.2 g, 0.68 mmol) is dissolved in DMSO (2.5 ml). The solution is cooled into an ice bath causing its solidification. 1.6 M BuLi solution in hexane (0.4 mmol) is added, and the temperature is allowed to heat to room temperature. Then MeI (0.25 mmol) is added. The reaction mixture is stirred until we get BODV (HPLC monitoring).

Example 6

BDDMV (0.5 g, 1.67 mmol) is suspended in CH₂Cl₂. Methyl Iodide (2.65 mmol) and Triethylamine (2.9 mmol) are added. The reaction mixture is stirred under nitrogen atmosphere at room temperature for 6 hours. At this stage MeI (5 mmol) and NEt₃ (3 ml) are added. The addition caused the temperature to rise. After 16 hours, the analysis shows the presence of BODV.

Preparation of ODV from BODV

Example 7 Preparation of Supported AgNO₃

To a solution of AgNO₃ (3.38 g in 100 ml H₂O), montmorillonite K10 (15 g) was added and the mixture was stirred for 30 min. at ambient temperature. The solution was then evaporated to dryness and the residue was dried in an oven at 100° C. for 1 hour.

0.4 g of BODV (1.26 mmol), 0.2 g of NaOH (5 mmol) and 2 g of supported AgNO₃ were mixed thoroughly in a mortar. The mixture was heated to 100° C. overnight under mechanical stirring. The mixture was then extracted with chloroform and with methanol to get ODV.

Example 8

A 100 ml three-necked flask equipped with nitrogen inlet, thermometer, mechanical stirrer and condenser was charged with Mg (0.2 g, 8.23 mmol) and 12 (0.1 g 0.39 mmol). BODV (0.3 g, 0.92 mmol) in THF (30 ml) was added dropwise and the mixture was heated to reflux for 1 hour. The mixture was cooled to −10° C. and trimethylborate (1 ml, 8.8 mmol) was added. After stirring for 30 min glacial acetic acid (2 ml, 34.9 mmol) was added. Then a cold solution of 30% hydrogen peroxide (2 ml 19.64 mmol) was also added. Diethylether was added and the organic phase was filtered to get ODV.

Preparation of BODV-P Example 9

A 100 ml three-necked flask equipped with Nitrogen inlet, thermometer, mechanical stirred and condenser was charged with BODV (0.37 g 1.13 mmol), EtOAc (20 ml) and Et₃N (1 ml 7.16 mmol). Acetylchloride (1 ml 14 mmol) was added slowly. The reaction mixture was stirred 1 hour at ambient temperature and the organic phase was washed with water, dried over magnesium sulfate and evaporated to get BODV-P.

Preparation of ODV from BODV-P

Example 10

A 250 ml three-necked flask equipped with Nitrogen inlet, thermometer, mechanical stirred and condenser was charged with Mg (0.7 g, 28.80 mmol) and 12 (0.2 g 0.78 mmol). BODV-P (1 g, 2.71 mmol) in THF (30 ml) was added dropwise and the mixture was heated to reflux for 2 hours. The mixture was then cooled to −10° C. and trimethylborate (20 ml, 176 mmol) was added. After stirring for 30 min at this temperature glacial acetic acid (15 ml, 261.75 mmol) was added. Then a cold solution of 30% hydrogen peroxide (20 ml 196.4 mmol) was added. The organic phase was washed with saturated ferrous ammonium sulfate, dried over magnesium sulfate and concentrated to get ODV.

Example 11 Preparation of Supported AgNO₃

To a solution of AgNO₃ (3.38 g in 100 ml H₂O), montmorillonite K10 (15 g) is added and the mixture is stirred for 30 min. at ambient temperature. The solution is then evaporated to dryness and the residue is dried in an oven at 100° C. for 1 hour.

0.4 g of P-BODV, 0.2 g of NaOH (5 mmol) and 2 g of supported AgNO₃ are mixed thoroughly in a mortar. The mixture is heated to 100° C. overnight under mechanical stirring. The mixture is then extracted with chloroform and with methanol to get ODV. 

1. (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC). 2-3. (canceled)
 4. A process for preparing compound of claim 1, 2 or 3 comprising reacting BBC with cyclohexanone.
 5. The process of claim 4, wherein the process comprises combining bromophenylacetonitrile (BBC), an organic solvent, a base and cyclohexanone to precipitating CBBC.
 6. The process of claim 5, wherein the organic solvent is selected from the group consisting of: C₂₋₈ ethers, polar aprotic solvents (Polarity Index of greater than about 2.0), C₁-C₈ chlorinated aliphatic and aromatic, C₆-C₁₂ aromatic hydrocarbons, and C₁₋₆ alcohols.
 7. The process of claim 5, wherein the organic solvent is selected from the group consisting of diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), methylene chloride, chlorobenzene, toluene and benzene.
 8. The process of claim 5, wherein the organic solvent is selected from the group consisting of tetrahydrofuran (THF), methanol, methylene chloride and toluene.
 9. The process of claim 5, wherein the organic solvent contains less than 1% water by volume.
 10. The process of claim 5, wherein the base is an alkali metal or alkaline earth metal.
 11. The process of claim 5, wherein the base is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis(trimethyl silyl) amide (LiN[(CH₃)₃Si]₂), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH₃).
 12. The process of claim 5, wherein the process is carried out by combining a solution or a slurry of BBC and a dry organic solvent with a base to obtain a reaction mixture, followed by combining the reaction mixture with cyclohexanone, to obtain CBBC.
 13. The process of claim 5, further comprising recovering CBBC.
 14. The process of claim 13, wherein recovery comprises evaporating the solvent, dissolving the residue in a water immiscible solvent such as toluene, washing with water or brine, and evaporated to get a residue.
 15. The process of claim 13, further comprising crystallizing CBBC from the residue.
 16. The process of claim 4, wherein the process comprises combining bromophenylacetonitrile (BBC), a phase transfer catalyst, optionally a base and cyclohexanone.
 17. The process of claim 16, wherein the reaction occurs in the presence of water.
 18. The process of claim 16, wherein the phase transfer catalyst is a tetraalkylammonium, tetraalkylphosphonium, tetraarylammonium or tetraarylphosphonium, wherein the alkyl group can be the same or different and contains from 1 to 10 carbons, and wherein the aryl group can be the same or different and contains from 6 to 8 carbons
 19. The process of claim 16, wherein the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot, quaternary ammonium salt, quaternary phosphonium salt and crown ether.
 20. The process of claim 16, wherein the phase transfer catalyst is tetra butyl ammonium bromide (TBAB).
 21. The process of claim 5, wherein the base is an alkali metal or alkaline earth metal hydroxide or carbonate.
 22. The process of claim 16, wherein the base is NaOH, KOH, LiOH, CsOH, K₂CO₃, NaCO₃ or Cs₂CO₃
 23. A process for preparing O-desmethylvenlafaxine comprising preparing CBBC as described in claim 4, and further converting the CBBC to O-desmethylvenlafaxine.
 24. 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV). 25-26. (canceled)
 27. A process for preparing a compound according to claim 24 comprising reacting CBBC with a reducing agent. 28-37. (canceled)
 38. 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). 39-40. (canceled)
 41. A process for preparing the compound of claim 38 comprising combining BDDMV, formaldehyde and a reducing agent. 42-46. (canceled)
 47. A process for preparing the compound of claim 38 comprising combining BDDMV, an organic solvent, and a methylating agent. 48-55. (canceled)
 56. A process for preparing O-desmethylvenlafaxine comprising preparing BODV according to claim 47, and further converting the BODV to O-desmethylvenlafaxine.
 57. A process for preparing O-desmethylvenlafaxine comprising hydrolyzing BODV of claim
 38. 58. A process for preparing O-desmethylvenlafaxine comprising: combining BODV of claim 38, a hydroxide donor base and a metal salt to obtain a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture. 59-65. (canceled)
 66. A process for preparing O-desmethylvenlafaxine comprising combining BODV of claim 38 with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocuprate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine. 67-72. (canceled)
 73. The process of any of claims 56-58 and 66 which synthesize O-desmethylvenlafaxine, wherein a hydroxyl protected BODV is used to synthesize O-desmethylvenlafaxine. 74-75. (canceled)
 76. Hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P). 77-80. (canceled)
 81. A process for preparing the hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) of claim 76 comprising combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture. 82-85. (canceled)
 86. A process for preparing O-desmethylvenlafaxine comprising preparing BODV according to claim 41, and further converting the BODV to O-desmethylvenlafaxine 